There is evidence that smoking is becoming concentrated in populations who because of various risk factors, are more likely to initiate smoking or have greater difficulty quitting. One of the best documented of these cofactors is depression. Numerous observers have noted clear manifestations of depression and dysphoria in women with a history of Major Depressive Disorder (Hx+ MDD) when they attempt to quit smoking. The long-term objective is to characterize and possibly modify response patterns that constitute a diathesis for smoking. Based on the literature and our own pilot data, we postulate that the reinforcing value of nicotine self-administration is enhanced in Hx+ MDD by the drug's affect- normalizing properties and its ability to protect against the hypothalamic-pituitary-adrenal (HPA) axis dysregulation that often characterizes episodes of depression, as indicated by elevated cortisol and ACTH levels following dexamethasone administration, an effect that is most pronounced in postmenopausal women. The specific aims are to 1) trace the time course and severity of depressive symptomatology in Hx+ MDD and Hx- MDD women smokers across different age categories when they abstain from smoking; 2) determine susceptibility to induction of depressed mood in Hx+ MDD and Hx- MDD women smokers; 3) elucidate key biobehavioral mechanisms underlying the relationship between dysphoria and use of nicotine; and 4) determine the extent to which pharmacological manipulations can relieve abstinence- induced depression/dysphoria and concomitant HPA axis dysregulation. The research design employs both within-subject and between-group comparisons in two interlocking studies, involving within-subject and between-group comparisons of women smokers and carefully assessing both psychological distress and neuroendocrinological dysfunction. STUDY I will assess the effects of nicotine vs. placebo patch during a week of smoking abstinence on cognitive and neuroendocrinological variables. STUDY II will investigate the ability of the antidepressant fluoxetine vs. placebo to ameliorate depression/dysphoria and restore HPA-axis function during smoking abstinence. HEALTH IMPLICATIONS: Depression is a major women's public health problem in its own right, taking an enormous toll in terms of lost productivity and diminished quality of life. To the extent that it increases the likelihood of initiation and maintenance smoking, the health consequences are magnified---as underscored by the fact that lung cancer has now surpassed breast cancer as the leading cause of cancer death in women. A better understanding of the reinforcing effects of smoking, and the mechanisms underlying these effects in depression-prone smokers, may lead to the development of rational prevention and cessation strategies tailored to the special needs of this large at-risk population.